1. Field of the Invention
The present invention relates to introverted cucurbituril CB[n] compounds and/or derivatives, and methods of making and using the same as well as to an improved synthesis of higher cucurbituril compounds.
2. Description of the Background
Cucurbituril (CB[n]) compounds are macrocyclic compounds containing glycouril repeat units, and afford an advantageous alternative to cyclodextrins in creating supramolecular constructs. Cucurbiturils were first synthesized in 1905 by Behrend, although the molecular structure thereof was not elucidated until 1981. Later synthetic efforts to prepare CB[n] compounds demonstrated the complexity and unreliability of conventional preparatory methods. See Day et al. J., Org. Chem. 2001, 8094-8100, and Lee et al., Acc. Chem. Res. 2003, 621-630. Kim et al. J.A.C.S. 2000, 122, 540-541. More recently, reliance on a methylene-bridged glycouril dimer substructure as the fundamental building block of CB[n] compounds has led to an unprecedented level of control in the synthesis of CB[n] compounds and their internal cavity volumes. See U.S. application Ser. No. 10,933,538, incorporated herein in the entirety.
Generally, CB[n] compounds have the formula shown in FIG. 1(a): wherein in the CB[n] formula, corresponding n values are shown for exemplary CB[n] compounds CB[5]-CB[8].
Also known are certain CB[n] derivatives shown in FIG. 1(b), wherein in the CB[n] formula, corresponding n values are shown for exemplary derivatives CB[5] and CB[6].
Importantly, in all of the known CB[n] compounds or CB[n] derivatives, all functional groups point outward from the CB[n] molecule as shown in FIGS. 1(a) and 1(b). That is, the functional groups protrude from the external surface of the molecule into exo-molecular space. However, it would be advantageous to be able to prepare CB[n] compounds or CB[n] derivatives having functional groups that point into the molecular cavity, i.e., inverted CB[n] compounds or CB[n] derivatives.
Inverted CB[n] compounds or CB[n] derivatives would, in fact, provide numerous advantages, such as:                1) Functional groups which point into the cavity of a cucurbituril compound which would enable:                    a) monitoring of complexation by 1H NMR spectroscopy of H-atoms, for example, pointing into the CB[n] internal cavity, and            b) use of introverted functional groups to enhance binding and/or catalytic processes in a manner similar to enzymes.                        2) Fine tuning (on the angstrom length scale) of the size of the cavity of the cucurbituril, which is not possible with the known “extroverted” cucurbiturils having functional groups on the external molecular surface.        3) Two ureidyl carbonyl functional groups of monointroverted CB[6], for example, which are exposed to solvent which indicates that they may undergo selective functionalization reactions which would enable:                    a) their selective derivatization to thiourea, guanidinium, and other functional groups, and            b) their attachment to suitable solid phases e.g. resin beads, silica gels, and surfaces.                        4) Monointroverted CB[6] is thermodynamically less stable that CB(6) itself, for example, which enables the investigation of its chemistry with potential application in the following areas:                    a) the mechanism of CB[n] formulation,            b) the selective production of mono- and multiply functionalized CB[n], and of bis, tris, and multiply covalently connected CB[n], by tailor-made synthetic approaches, and            c) the production of fragments of the cucurbit[n]uril skeleton which may have binding properties as unusual as the CB[n] family themselves.                        
However, to date such introverted CB[n] compounds and derivatives have been unknown.
Thus, a need exists for inverted CB[n] compounds and/or CB[n] derivatives which would have the structural and reactive characteristics noted above, and which could be prepared in a reliable manner.